Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference, in its entirety and for all purposes, in this document.
Pancreatic ductal adenocarcinoma (PDAC) affects 44,000 individuals yearly in the United States. Almost universally, this cancer is lethal, with very limited efficacy of chemotherapy (gemcitabine, nab-paclitaxel, platinum, 5FU). Clinical trials addressing this glaring need for expanded portfolio of anti-cancer agents active in PDAC have been unsuccessful, and a lack of active agents has blocked progress in improving survival rates for pancreatic cancer. Transformative new therapies are urgently needed for this devastating malignancy, which is understood to be nearly universally driven by “undruggable” and interdependent mutations in KRAS, P53 and MYC.
Oncogenic MYC is amplified in from 8% to as high as 30% of PDAC. MYC expression is directly regulated by multiple KRAS effectors, so that phosphorylation of Serine-62 by ERK stabilizes MYC, whereas subsequent phosphorylation of Threonine-58 by GSK3b (which is inhibited by AKT) is required for MYC ubiquitin-mediated degradation. In addition to MYC's ability to function as a bHLH transcriptional factor, MYC causes transcription amplification. Tumors expressing high MYC levels show increased levels of MYC in the promoter regions of actively transcribed genes. Frequent amplification of c-Myc in human cancers has been the focus of investigation, but it is believed that no effective way to curtail viability of c-Myc-dependent cancers has yet been uncovered.
Mechanistically, suppressing MYC necessitates shutting down the pre-existing oncogenic transcriptional program including the MYC gene itself. This is achievable through interference with various components of RNA Pol II complex. The choice of anti-MYC targets, however, remains limited.